Bioactive Natural Products from Chinese Marine Flora and Fauna

Acta Pharmacologica Sinica (2012) 33: 1159–1169 npg © 2012 CPS and SIMM All rights reserved 1671-4083/12 $32.00 www.nature.com/aps Review Bioactive natural products from Chinese marine flora and fauna Zhen-fang ZHOU, Yue-wei GUO* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail. Keywords: marine natural products; biological activity; mangrove; algae; soft coral; sponges; mollusks Acta Pharmacologica Sinica (2012) 33: 1159–1169; doi: 10.1038/aps.2012.110; published online 3 Sep 2012 Introduction ment of Chinese marine natural products. This review sum- The unique ocean habitat has caused marine organisms to marizes the progress and achievements made by our group evolve distinctive metabolic pathways, producing remark- in the study of Chinese marine flora and fauna in the past able secondary metabolites that differ from those of terrestrial decade, and several interesting examples are discussed in plants. Because the compounds isolated from marine organ- detail. isms are structurally and biologically intriguing, research on marine natural products has been attracting the attention of Chemical studies on Chinese marine plants chemists as a challenging research topic. To date, more than Algae 30 000 compounds bearing unusual structures and exhibiting Microalgae play important roles in marine biological systems. various bioactivities have been isolated from marine plants Through their photosynthetic ability, algae are the major pro- and invertebrates. ducers of biomass and organic compounds in the ocean. More In recent years, the interest in natural products from Chi- importantly, many algal metabolites present unique structures nese marine organisms has increased dramatically, mak- and are formed via biosynthetic routes that are quite different ing the annual average number of natural products isolated from those known to produce terrestrial metabolites. from marine organisms increase rapidly. As one of the most Marine dinoflagellates are flagellated organisms with both active research groups in this area, we have been devoted to photosynthetic and heterotrophic attributes. The lifestyle of the investigation of Chinese marine plants and invertebrates these organisms is diverse, and many of them participate in since 2000. In the course of our studies, a series of structurally symbiotic relationships. For some time, the study of dinofla- diverse and biologically interesting compounds belonging to gellates has focused on their toxin production and pigment various structural classes, such as macrocyclic polydisulfides, composition, and only a small number of these organisms have spirodioxynaphthalene, and alkaloids, have been isolated and been found to produce other secondary metabolites. As part characterized. Through these productive studies, we have of our ongoing research on the biologically active substances made important contributions to the research and develop- of Chinese marine organisms, three new polyhydroxylpolyene compounds, lingshuiols A and B (1 and 2) and lingshuiol (3), have been isolated from the Chinese marine dinoflagellate * To whom correspondence should be addressed. E-mail [email protected] Amphidinium sp collected at Lingshui Bay, Hainan Province, Received 2012-06-17 Accepted 2012-07-12 China[1, 2] (Figure 1). The structures of these compounds are npg www.nature.com/aps Zhou ZF et al 1160 Figure 1. Structures of polyhydroxylpolyene compounds 1–3. characterized by linear carbon chains, as determined by extensive analyses of 2D NMR spectroscopic data; however, the absolute configurations remain to be determined. In previ- ous studies, polyhydroxylpolyene compounds were found to exhibit antifungal, hemolytic, and antimicrobial activities[3–5]. It was demonstrated that lingshuiol (3) possessed potent in vitro cytotoxic activities against A549 and HL-60 cells, with IC50 values of 0.21 and 0.23 µmol/L, respectively. Red algae of the genus Laurencia are found throughout the world, mostly in tropical and subtropical regions. Since Irie’s pioneering investigations on Laurencia over the last four decades[6], a number of cuparene- and laurane-derived sesquiterpenoids have been isolated from this genus. The chemi- Figure 2. Structures of sesquiterpenes 4–8. cal investigation of the Chinese red alga Laurencia okamurai Yamada led to the isolation of a new laurane sesquiterpenoid, 3β-hydroxyaplysin (4), and two novel rearranged sesquiter- (laurene type) or 1,2,2 (cuparene type), with the exception of penes, laurokamurenes A and B (5 and 6)[7] (Figure 2). Their laurokamurenes A and B (5 and 6). structures, including their relative stereochemistry, were Two novel aromatic valerenane-type sesquiterpenes, cauler- determined based on a detailed interpretation of 2D NMR pals A and B (7 and 8), were isolated from the Chinese green spectra and comparisons with related known compounds. To alga Caulerpa taxifolia[9] (Figure 2). Compounds 7 and 8 were the best of our knowledge, this is also the first report of the evaluated for their inhibitory activity against human protein isolation of sesquiterpenes containing a 2,2,3-trimethylcyclo- tyrosine phosphatase 1B (PTP1B), a potential drug target pentenyl moiety from a natural source. The sesquiterpenoids for the treatment of type 2 diabetes and obesity, but neither isolated from the red algae of the genus Laurencia in recent compound exhibited a potent PTP1B inhibitory activity. It years can be classified into more than 20 sesquiterpenoid is important to note that caulerpals A and B (7 and 8) are the skeletons[8]. However, in most cases, the three methyl groups only two known compounds with an aromatic valerenane- in the aliphatic portion are located at either positions 1,2,3 type carbon skeleton from a natural source. Acta Pharmacologica Sinica www.chinaphar.com npg Zhou ZF et al 1161 Mangroves Mangroves comprise a large number of various salt-tolerant plants growing in tropical and subtropical intertidal estuarine zones. Mangrove plants are usually categorized into two subgroups, true mangrove and semi-mangrove plants, accord- ing to their living environment. True mangrove plants are confined to the typical intertidal mangrove habitats where the seawater salinity is usually 17.0‰–36.4‰. Semi-mangrove plants, however, grow on the landward fringe of the mangrove habitats or in the terrestrial marginal zones that are sub- jected to irregularly high tides. In general, mangrove plants consist of 84 species globally, belonging to 24 genera and 16 families; 14 are semi-mangrove species[10, 11]. Most of our studies involve plants belonging to the Rhizo- phoraceae, Sonneratiaceae, Euphorbiaceae, and Meliaceae families. A series of unusual compounds bearing unprece- dented structures were identified in these taxa, some of which showed marked biological activities and are currently in pre- clinical studies. For instance, an unusual novel macrocyclic polydisulfide gymnorrhizol (9) was isolated from the mangrove plant Bru- guiera gymnorrhiza (Rhizophoraceae family). Compound 9 possesses an uncommon carbon skeleton that is character- istic of a 15-membered macrocycle composed of 3 repeated 1,3-dimercaptopropan-2-ol units[12] (Figure 3). The structure of compound 9 was established by extensive spectroscopic studies and confirmed using X-ray crystallography[13]. The first total synthesis of gymnorrhizol (9) was completed by our group with a high overall yield[14] (Scheme 1). Prompted by the unusual structure of gymnorrhizol (9) and its potent inhibitory activity against PTP1B (an IC50 value of 14.9 µmol/L), we investigated the same mangrove species collected from different areas, which led to the isolation of two new macrocyclic polydisulfides, 10 and 11[15]. The structures of 10 and 11 were unequivocally determined through single- crystal X-ray diffraction analysis. A plausible biosynthetic pathway for these cyclic polydisul- Figure 3. Structures of macrocyclic polydisulﬁdes 9–11 and their X-rays. fides was also proposed in which the 1,3-dimercaptopropan- 2-ol unit should be the common building block for the bio- synthesis of all of these macrocyclic polydisulfides; the self- sizes gave rise to macrocyclic polydisulfides ranging from cyclization of the 1,3-dimercaptopropan-2-ol unit of different 5-membered to 30-membered polydisulfides or even to larger Scheme 1. Total synthesis of gymnorrhizol (9). Acta Pharmacologica Sinica npg www.nature.com/aps Zhou ZF et al 1162 polydisulfides. Marine disulfide- and multisulfide-containing metabolites are a special and important class of natural products. Due to the

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